1. Field of the Invention
The invention relates to methods of preparing and using nutrient compositions for parenteral administration. More specifically, the invention relates to methods and uses of stable, dry-packaged, sterile, nutrient compositions which upon addition of water are suitable for intravenous administration to mammals.
2. Brief Description of the Prior Art
Prior hereto, commercially available parenteral nutrient compositions were generally prepared in the form of aqueous solutions employing highly sophisticated and costly manufacturing plant facilities. Because of their cost, these facilities are few in number and located long distances from the majority of sites where the solutions are required for use. Accordingly, added costs are generated by the need to transport the aqueous solutions to distant points of use such as hospitals, clinics and like medical facilities.
The need for centralized, costly facilities for preparing parenteral nutrient compositions has been dictated by the need to prepare these compositions ready to use, i.e.; in the form of aqueous solutions meeting the stringent requirements for intravenous administration to a human. This need has been generated over recent years by increasingly stringent standards of sterility, non-pyrogenicity and freedom from extraneous particulate matter, imposed by regulatory health agencies. In fact, the standards now set are of such a high level that as a practical matter they could, heretofore, be achieved economically only at the complex and costly plant facilities referred to above.
There are a number of obvious and not so obvious disadvantages associated with the prior art system for supplying parenteral nutrient compositions at the point of use. Most obvious is the disadvantage of having to store and ship large volumes and weights of water, the major constituent of the parenteral solution. It has been proposed heretofore to prepare the nutrient compositions in a dry-packaged form for shipment to the point of use; see for example U.S. Pat. No. 3,648,697. At the point of use, sterile water is mixed with the dry compositions, to form the solution at the site of use and obviate the storage and shipment of large quantities of water. Unfortunately, the proposal to package and ship dry forms of parenteral compositions has not had commercial success. One of the major reasons for the lack of success has been the inability to produce at the site of use, an aqueous solution of the dry form, which will meet the stringent requirements of sterility, non-pyrogenicity and freedom from particulate matter. This has been due in part to a lack of a method which will provide the dry nutrient composition themselves in a state of acceptable sterility and purity. Even if sterile, pyrogen-free water is available at the site of use for mixing with a dry form of the nutrient composition, the product upon admixture generally has not been satisfactory, failing to meet standards.
By the method of our invention, highly stable, dry-packaged, sterile, pyrogen-free nutrient compositions are provided which upon the addition of sterile, pyrogen-free water will yield solutions of the nutrients meeting the criteria for safe intravenous administration to a human.
In addition, the method of the invention obviates a number of other problems associated with the prior art system of preparing parenteral nutrient solutions, which comprises sterilization by autoclaving. The parenteral solutions are packaged and then subjected to autoclaving to assure sterility. Autoclaving as a method of sterilization permits only certain nutrients to be present in the same solution during sterilization because of the chemical reactivity of these materials under autoclave conditions. For example, amino acids and reducing sugars such as dextrose will combine in a Maillard reaction to form Amadori compounds which are potentially toxic and largely non-utilizable especially when infused intravenously. A further example of the limitation imposed by the prior art method of autoclave sterilization is encountered in regard to vitamins. The autoclave conditions are too severe for many vitamins such as, for example, thiamine, riboflavin, ascorbic acid and the like. These vitamins in particular are rapidly degraded to less than 10 percent of their initial activity when exposed to autoclave conditions and stored in aqueous solution, even for short periods of time.
Further, inherent in autoclave sterilization is a limitation of effectiveness of the method itself. Deaths of patients have been reported and traced to inability to achieve sterile conditions in a number of instances. This is particularly true of the present commercially available solution package, which includes a stopper and a metal cap to secure the stopper to the solution container. It is difficult to achieve sterilizing conditions lethal to bacteria under the metal cap, which is designed to protect the stopper from contamination. It is difficult for sufficient moisture at elevated temperatures to penetrate around the metal cap and sterilize the stopper. Another problem inherent in the use of autoclave as a means of sterilizing is in the use of certain plastic containers for parenteral solutions, wherein autoclave conditions can cause chemical interaction between the plastic formulations and the contained solutions.
By the method of the present invention, many of the problems associated with autoclave sterilization are obviated. For example, many patients require complex solutions containing amino acids, monosaccharides, fats, vitamins, macro-minerals and trace minerals to be administered to them intravenously. Because of the current technology described above, these nutients must be made available to the patient in a plurality of containers. For example, one common method is to provide a bottle of amino acid solution, a bottle of glucose, a bottle of multivitamins and separate bottles with a mineral nutrient in each or a mixture of minerals. A hospital pharmacist or intravenous solution technician then has the responsibility for adding these nutrients together under sterile conditions. This process is laborious and potentially dangerous. Also, it is almost impossible to end up with an exact concentration of final solution because it is difficult to calculate the final solution volume after adding a plurality of nutrient materials. By the method of our invention, heretofore unstable and imcompatible drugs and nutrients are conveniently packaged in a single container, in sterile, pyrogen-free condition for ultimate administration to the patient.
The dry-packaged products produced by the method of our invention greatly extend the flexible use of parenteral solutions in nutrient therapy. The method of our invention permits the safe, economic deliverability of simple and complex intravenous solutions at the patient's bedside.